Alzheimer?s disease (AD) is the most common cause of dementia in the elderly. The pathogenesis of AD is unclear but involves the formation of aggregated a-amyloid peptides (Aa) in the brain. Research on antiamyloid therapy has shown potential to treat AD, and the development of anti-amyloid therapies may be facilitated by the use of 2-arylbenzothiazole amyloid imaging agents such as Pittsburgh Compound-B (PIB). Once therapies are in hand, tracers such as PIB could be even more useful for identifying preclinical cases of AD as candidates for early intervention and to follow the effectiveness of therapy in individual patients. Unfortunately, the 11C label on PIB limits its use to highly sophisticated academic PET (positron emission tomography) facilities (<10 % of all PET facilities). 18F derivatives of PIB have recently been developed and could increase the availability of amyloid imaging to all PET facilities, but this still represents a minority of modern hospitals, as only a small fraction of hospitals have a PET scanner. However, many more hospitals have the capacity to perform single photon emission computed tomography (SPECT). Our long-term goal is to develop an Aa radiotracer which can be prepared easily at minimal cost, and has widespread clinical applicability via the use of the convenient and cost-effective imaging modality, SPECT. In this proposed research, we will investigate the potential of 99mTc-labeled 2-arylbenzothiazoles as Aa imaging agents. 99mTc is an inexpensive and readily available diagnostic radioisotope. Many 2- arylbenzothiazole derivatives have high binding affinity to aggregated Aa. 99mTc-labeled derivatives of 2- arylbenzothiazole may be ideal radiotracers for imaging Aa burden with SPECT. Since there is no stable isotope of Tc available, we will use Re, a congener of Tc, as a surrogate. First we will design and synthesize compact, neutral and lipophilic Re-containing derivatives of 2-arylbenzothiazole with high binding affinity to aggregated Aa. Complexation of 2-arylbenzothiazoles with Re will be achieved via the use of an integrated chelating system to minimize the overall molecular size. We will evaluate the potential of Recontaining derivatives of 2-arylbenzothiazole based on their lipophilicity and binding affinity to aggregated Aa. We will then translate promising Re-containing derivatives of 2-arylbenzothiazole into promising 99mTclabeled 2-arylbenzothiazoles, and assess the suitability of these 99mTc analogs for clinical imaging by determining brain entry and clearance in mice. The data generated by this proposed research will provide us invaluable structure-activity relationship information for the development of 99mTc-labeled Aa imaging agents which could be used for early diagnosis of Alzheimer?s disease and facilitating the development and application of anti-amyloid therapy. Project